The present invention relates to novel-cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides; to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in vitro and in vivo.
Cationic lipids and the use of cationic lipids in lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA, have been previously disclosed. Lipid nanoparticles and use of lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA, has been previously disclosed. Oligonucleotides (including siRNA and miRNA) and the synthesis of oligonucleotides has been previously disclosed. (See US patent applications: US 2006/0083780, US 2006/0240554, US 2008/0020058, US 2009/0263407 and US 2009/0285881 and PCT patent applications: WO 2009/086558, WO2009/127060, WO2009/132131, WO2010/042877, WO2010/054384, WO2010/054401, WO2010/054405 and WO2010/054406). See also Semple S. C. et al., Rational design of cationic lipids for siRNA delivery, Nature Biotechnology, published online 17 Jan. 2010; doi:10.1038/nbt.1602.
Butyl CLinDMA is one of the cationic lipids disclosed in US 2006/0240554. Other cationic lipids are also generically disclosed in US 2006/0240554 including Octyl CLinDMA. We have synthesized and tested both Butyl CLinDMA and Octyl CLinDMA in lipid nanoparticle formulations and found that Octyl CLinDMA has superior properties to Butyl CLinDMA. Octyl CLinDMA (otherwise known as OCD) is also described in WO02010/021865.
We adopted a rational approach to design cationic lipids for use in lipid nanoparticle formulations to deliver small interfering RNA (siRNA). Starting with the cationic lipid Octyl CLinDMA (designated, “Compound 12” in this application) as a benchmark, we designed novel cationic lipids with superior properties as demonstrated in mouse, rat and monkey experiments.
The compounds of the instant invention contain a 1,3-diether linker.
It is an object of the instant invention to provide novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides, to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in vitro and in vivo.